Method of cell surface activation and inhibition

Abstract

Disclosed are methods of cell surface activation and inhibition that involve the interaction of an inhibitor of matrix metalloprotease known as TIMP-2, with the enzyme, gelatinase-A (GelA). Critical to the methods of the invention is the discovery of a unique TIMP-2 binding site on the surface of the C-terminal domain (GelA-CTD) of the enzyme, which has been determined to be Asp656, but which can also included other residues in the GelA-CTD domain with which Asp656 forms a contiguous surface, namely Gly651, Phe650, and Tyr636 Identification of this binding site provides a useful target for the screening of MMP inhibitors and for prognosis and treatment of diseases in which MMPs are implicated. Compounds which are candidate MMP inhibitors can be structured to competitively inhibit cell surface activation.

What is claimed is: 
     
       1. A target area for screening MMP inhibitors consisting of a peptide of residues Tyr 636  to Asp 656  in the TIMP-2 binding site of the GelA-CTD domain as shown in FIG. 5 and in the Sequence Listing as residues 22 to 42 of SEQ ID NO:10. 
     
     
       2. A method of screening for MMP inhibitors comprising determining the effect of a test compound on cell surface activation and inhibition upon reaction of said test compound at the target area of claim 1.